Why aspirin doesn't always stop blood clots

Aspirin’s blood-thinning properties are well known, making it the drug of choice for protection against blood clots in heart disease. But it doesn’t work for everyone: some people are aspirin resistant and continue to develop clots. Now, Spanish cardiovascular researchers led by Carlos Macaya at Madrid’s San Carlos Hospital Clinic have linked aspirin resistance to a protein that binds vitamin D.

Aspirin, acetylsalicylic acid, thins blood because it stops platelets - the cells involved in blood-clot formation - from aggregating. The drug blocks the synthesis of thromboxane A₂ (an eicosanoid related to the prostaglandin family of lipids), which activates the formation of platelets, making them stick together. Thromboxane A₂  synthesis is blocked by irreversibly inhibiting the action of an enzyme called cyclooxygenase-1 (COX-1).

COX-1 activity is not blocked in aspirin-resistant patients, but reasons for this had remained unclear. It was thought that resistant patients might carry aspirin-resistant COX-1 gene mutations, or that the patients’ vascular systems and how their platelets interact with other cells in blood plasma might have been modified.  

The Spanish team conducted a trial with 19 aspirin-sensitive and 19 aspirin-resistant patients who had experienced recent acute coronary ischemic events. They used proteomics techniques to look at different blood-serum proteins expressed by the two patient groups.

Two-dimensional gel electrophoresis was used to separate and identify the proteins. The protein mix was first separated according to charge, then the gel was rotated through 90^o and the proteins separated by mass. 

Macaya’s team found that aspirin-resistant patients’ serum contained raised levels of a vitamin D-binding protein (DBP) in three fully functional versions. When this protein was incubated with blood from healthy volunteers, it significantly reduced aspirin’s inhibitory effect on platelet thromboxane A₂ production.

The Spanish team says this suggests a completely new mechanism for aspirin resistance. ’DBP might directly reduce aspirin’s ability to acetylate COX-1’s active site,’ said Macaya. ’Or DBP might bind platelet cytoskeleton proteins that change COX-1’s structure, making its active site less accessible to aspirin.’ 

Lionel Milgrom

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